This is a proposal to examine the genetic heterogenity of human brain proteins using high resolution two-dimensional gel electrophoresis. The pattern of proteins in 9 M urea and other extracts of 300 brains will be examined for the frequency of charge change or null mutations. The gels are standardized by the use of internal charge and molecular weight markers and many of the proteins will be identified by comparison with isolated specific brain proteins or fractions. The identification of mutations of brain proteins and their correlation with specific diseases will provide important insights into the genetics and pathogenesis of Huntington Disease affective psychoses, schizophrenia, the cerebellar ataxias, and many other hereditary neurological or behavioral disorders. We are especially interested in the possible role of mutations of CaM-BP80, a calmodulin binding protein present in highest concentrations in the caudate and putamen, in HD and schizophrenia. In addition, a mutation already identified Pcl Duarte, will be further examined. Initial studies strongly suggest an association of this mutation with severe depression, manic depression and alcoholic depression. We wish to collect and examine an additional 100 brains from individuals who have committed suicide and in whom a post-mortum diagnosis of severe affective disease can be substantiated, to see if this important correlation holds up with a different set of brains. Accident cases from the same geographical area will be used as controls.